Published online before print November 15, 2001, doi: 10.1161/hh0102.102272
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Submitted on July 31, 2001
Revised on October 23, 2001
Accepted on November 6, 2001
The Brain Renin-Angiotensin System in Transgenic Mice Carrying a Highly Regulated Human Renin Transgene
From the Departments of Medicine (S.M., C.D.S.), Physiology and Biophysics (C.D.S.), and Anatomy and Cell Biology (M.D.C.), University of Iowa, Iowa City, Iowa.
* To whom correspondence should be addressed. E-mail: curt-sigmund{at}uiowa.edu.
We previously reported the generation of 2 novel transgenic mouse models containing the human renin (hREN) gene encoded on P1 artificial chromosomes (PAC) containing large amounts of 5'-flanking DNA. These mice exhibit a very narrow tissue-specific expression profile and exhibit tightly regulated expression in kidney in response to physiological cues. In brain, transcription of hREN occurs from an alternative upstream promoter, causing translation to initiate within exon-II and potentially generating an intracellular form of active renin. Double transgenic mice containing a PAC transgene and the human angiotensinogen (hAGT) gene (P+/A+) are moderately hypertensive. We tested whether increased RAS activity in the brain contributes to the mechanism of hypertension in P+/A+ double transgenic mice. Expression of hREN mRNA in brain was confirmed in 4 independent PAC transgenic lines and utilization of the alternative transcription start site in brain was confirmed in each line. Human REN immunostaining was observed in the dorsal cochlear nucleus, hypothalamus, and cortex. P+/A+ mice exhibited a greater fall in mean arterial pressure after intracerebroventricular injection of losartan than controls. P+/A+ mice exhibited a greater drop in arterial pressure after interventricular injection of a vasopressin V1 receptor antagonist, and an equivalent drop in arterial pressure after interventricular injection of a ganglion blocker compared with controls. These results support the hypothesis that renin is endogenously expressed in the brain and suggest that increased brain RAS activity may contribute to the maintenance of moderate hypertension in P+/A+ transgenic mice at least in part by a vasopressin-dependent mechanism.
Key words: renin-angiotensin system • blood pressure • vasopressin • sympathetic nerve activity • central nervous system • transgenic mice
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